IgE(immunoglobulin E) is, despite its normally very low concentration in human plasma (10-400 ng/ml), a major cause of hypersensitivities found within the human population. This property is due to its interaction with the high-affinity receptor for IgE on mast cells and basophilic leucocytes.
Cross-linking of two IgE receptors on the surface of these cell types, by allergen binding, initiates the release of a number of physiologically active substances such as histamine, PAF (platelet activating factor), heparin, chemotactic factors for eosinophilic and neutrophilic granulocytes, leucotrienes, prostaglandins and thromboxanes. It is these mediators which cause the direct symptoms of IgE-mediated allergic reactions (Type I hypersensitivity). Disease conditions belonging to this group include most types of asthma, fur allergies, pollen allergies, many types of food allergies and certain types of eczema.
The high-affinity receptor for IgE has been characterized on both protein and gene level in mouse, rat and man (Kinet et al. 1987; Shimizu et al. 1988; Tepler et al. 1989; Blank et al. 1989; Kinet et al. 1989). This receptor probably is present only on mast cells and basophilic leucocytes in our body. The receptor is a complex of three different subunits, the so-called .alpha., .beta. and .gamma. chains. It is the .alpha. chain localized mainly extracellularly which interacts with the IgE molecule.
Detailed studies regarding the region of the epsilon chain of the IgE molecule interacting with the high-affinity receptor for IgE have shown that a region of 76 amino acids at the border between the CH2 and CH3 domains (CH=constant domains in the heavy chain) is of decisive importance for the interaction between the IgE molecule and its high-affinity receptor.
This peptide has been shown, in vitro, to be able to inhibit the interaction between native IgE and its high-affinity receptor in a molar ratio of nearly 1:1 compared to the whole CH2-CH3-CH4 region (Helm et al., 1988). The peptide has also been shown to be able to inhibit an IgE-mediated flare reaction in allergen stimulation. However, in this case the concentration is about 10 times the concentration that with native IgE provides the same inhibiting effect (Helm et al., 1989).
When the IgE molecule binds to its receptor, certain regions of the epsilon chain will be blocked for interaction with other molecules, such as e.g. antibodies defected against epitopes within the same region of the IgE molecule. Then, the IgE antibody may only bind to either an IgG antibody directed against the CH2-CH3 region of the IgE molecule or to the receptor and thus never to both of these molecules simultaneously. Antibodies which bind to epitopes outside the region directly interacting with the receptor will, contrary to the ones mentioned previously, give rise to cross-linking of the IgE molecules which are bound to the surface of a mast cell. In this case one will have a very strong release of granula and an anaphylactic shock in the subject in which such an antibody is injected. The antibodies binding to the receptor-bindning portion will, to the contrary, not be able to cross-link these receptors and no immediate reaction arises but an effect of the more prolonged decrease of the concentration of freely circulating IgE. This will probably prevent granula release in that no IgE antibodies are present any longer in the plasma of the subject.
These anti-IgE antibodies will probably also more permanently knock out the IgE-producing B-cell population which increases the possibility to obtain a more long-lasting suppression of the IgE synthesis. During periods of potent pollen exposure, then the antibodies will bind and completely eliminate the pool of IgE which is the cause of the strong inflammatory reaction of pollen-allergic subjects. A number of observations indicate that non-allergic subjects have a relatively high concentration of endogenous anti-IgE antibodies which are believed to have a similar allergy-inhibiting effect.
The effect of the vaccine according to the invention is based on its ability to induce an immune response against the body's own IgE, which, owing to that, will prevent the binding of the IgE antibodies to these receptors. Owing to that, the release of the allergy-inducing substances stored in the mast celles will be prevented.